A prospective phase II, randomised multi-center trial of a biomodulatory treatment with metronomic low-dose treosulfan, pioglitazone and clarithromycin versus nivolumab in patients with lung cancer, after platin failure (ModuLung).

Most non-small cell lung cancers (NSCLCs) occur in elderly and frequently comorbid patients. Therefore, it is necessary to evaluate the efficacy of biomodulatory active therapy regimen, concertedly interfering with tumour-associated homeostatic pathways to achieve tumour control paralleled by modest toxicity profiles. 

The ModuLung trial is a national, multicentre, prospective, open-label, randomized phase II trial in patients with histologically confirmed stage IIIB/IV squamous (n=11) and non-squamous non-small cell (n=26) lung cancer (NSCLC) who failed first-line platinum-based chemotherapy. Patients were randomly assigned on a 1:1 ratio to the biomodulatory or control group, treated with nivolumab. Patients randomized to the biomodulatory group received an all-oral therapy consisting of treosulfan 250 mg twice daily, pioglitazone 45 mg once daily, clarithromycin 250 mg twice daily, until disease progression or unacceptable toxicity. 

The study had to be closed pre-maturely due to approval of immune checkpoint inhibitors in first-line treatment. Thirty-seven patients, available for analysis, were treated in second to forth-line. PFS was significantly inferior for biomodulation (N= 20) versus nivolumab (N= 17). ORR was 11.8% with nivolumab versus 5% with biomodulation. The frequency of grade 3 to 5 treatment related adverse events was 29% with nivolumab and 10% with biomodulation. OS, the secondary endpoint, was comparable in both treatment arms.